Adjunct gene therapy for coronary artery bypass surgery

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Coronary Artery Disease Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle (the coronary arteries) become hardened and narrowed due to buildup of a material called plaque on their inner walls in a process known as atherosclerosis. As the plaque increases in size, the insides of the coronary arteries get narrower and less blood can flow through them, and the heart muscle is starved of the oxygen it needs. This can result in angina, chest pain or discomfort and eventually the patient may suffer a heart attack. Cells in the heart muscle begin to die if they do not receive enough oxygen-rich blood causing permanent damage to the heart muscle. CAD is the most common type of heart disease and the leading cause of death in the United States and Europe for both men and women. Treatment For CAD A range of medicines combined with lifestyle changes are used to treat CAD initially. However, if the symptoms continue to worsen, then direct intervention by angioplasty or bypass surgery may be necessary. Angioplasty involves inflating a small balloon within the artery and pulling it through to remove the blockage, opening the narrowed coronary arteries. A device called a stent may then be placed in the artery to keep it propped open after the procedure. Alternatively, in cases where two or more arteries in the heart are blocked, coronary artery bypass graft (CABG) surgery may be necessary. In this procedure arteries or veins from other areas of the body, such as the saphenous vein from the leg, are used to bypass the narrowed coronary arteries, improving blood flow to the heart, relieving chest pain, and possibly preventing a heart attack. Vein Graft Failure in CABG CABG surgery is very effective but there is a high rate of longer-term failure. Vein grafts failure is caused by the manipulation of the vein during surgery and the exposure of the vein to the high blood pressure in the heart. After surgery the vein undergoes a repair process, which leads to a thickening of the wall of the vein. Some thickening is desirable to enable the graft to survive the high blood pressure in the heart. However, sometimes this thickening is excessive and can lead to accelerated atherosclerosis and restricted blood flow through the vein graft. There is no effective therapy available for vein graft failure and the only option is to repeat the CABG, which is a more hazardous process second time. Aims and Objectives We aim to develop gene-based treatment for vein grafts, which will be applied to the vein when it is outside the body, prior to insertion into the heart. To achieve that goal we have developed an efficient synthetic gene carrier formulation, based on a combination of genes, small pieces of protein (peptides), liposomes, which are fatty spheres that help deliver materials into cells. The formulation, called Liptide , is very efficient at inserting genes into the walls of blood vessels and has already demonstrated therapeutic efficacy in rabbits. Genes were delivered into vein grafts before surgery and one month later it was shown that vein graft thickening was less than half that of untreated controls. We now aim to develop this technology further in a large animal model, the pig, which is a better indicator of likely efficacy in man. This study will also develop tests and experiments for evaluating the safety of the treatment prior to clinical trials. Applications and Benefits Each year more than a million CABG procedures are performed. Unfortunately, although surgery is very effective, there is a high rate of longer-term graft failure with 15-20% of vein grafts failing within one year and 50% at 10 years, leading to further serious complications. An effective treatment to promote the survival of vein grafts could affect the lives of millions of patients. The same technology could then be applied to the treatment of other diseases with genes, including cancers.